Benzoate derivatives of diaryl 1,3,4-oxadiazolone

ABSTRACT

The present invention provides novel benzoate derivatives having the general formula ##STR1## wherein R is as defined herein, or a nontoxic pharmaceutically acceptable salt or solvate thereof and are useful in the treatment of disorders which are responsive to the opening of potassium channels.

CROSS-REFERENCE TO RELATED APPLICATION

This is a nonprovisional application which claims the benefit ofprovisional applications U.S. S. No. 60/107,486, filed Nov. 6, 1998, andU.S. S. No. 60/072,965, filed Jan. 29, 1998.

FIELD OF THE INVENTION

The present invention is directed to novel benzoate derivatives of a1,3,4-oxadiazol-2(3H)-one compound which is a modulator of thelarge-conductance calcium-activated potassium (BK) channels and,therefore, useful in the protection of neuronal cells and diseasesarising from dysfunction of cellular membrane polarization andconductance. The present invention also provides a method of treatmentwith the novel substituted oxadiazolone derivatives and topharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

Stroke is presently recognized as the third leading cause of adultdisability and death in the United States and Europe. In the pastdecade, several therapeutic approaches for the minimization ofstroke-related brain damage have been pursued including inhibitors ofAMPA/kainate, N-methyl-D-aspartate (NMDA) and adenosine reuptakeinhibitors. It is the object of the present invention to provide novelcompounds that will modulate potassium channels, in particular,large-conductance calcium-activated potassium (BK) channels which willbe useful in reducing neuronal damage during ischemic conditions of astroke episode.

Potassium channels play a key role in regulation of cell membranepotential and modulation of cell excitability. Potassium channels arethemselves regulated by voltage, cell metabolism, calcium ion andreceptor mediated processes. Cook, N. S., Trends in Pharmacol. Sciences,9, pp.21-28 (1988); and Quast, U. and Cook, N. S., Trends in Pharmacol.Sciences, 10, pp. 431-435 (1989)!. Calcium-activated potassium (K_(Ca))channels are a diverse group of ion channels that share a dependence onintracellular calcium ions for activity. The activity of K_(Ca) channelsis regulated by intracellular Ca²⁺ !, membrane potential andphosphorylation. On the basis of their single-channel conductances insymmetrical K⁺ solutions, K^(Ca) channels are divided into threesubclasses: large conductance (BK)>150 pS; intermediate conductance50-150 pS; small conductance <50 pS. ("pS" stands for picosiemen, a unitof electrical conductance.) Large-conductance calcium-activatedpotassium (BK) channels are present in many excitable cells includingneurons, cardiac cells and various types of smooth muscle cells. Singer,J. J. and Walsh, J. V., Pflugers Archiv., 408, pp. 98-111 (1987); Baro,I., and Escande, D., Pflugers Archiv., 414 (Suppl. 1), pp. S168-S170(1989); and Ahmed, F. et al., Br. J. Pharmacol., 83, pp. 227-233(1984)!.

Potassium ions play a dominant role in controlling the resting membranepotential in most excitable cells and in maintaining the transmembranevoltage near the K⁺ equilibrium potential (E_(k)) of about -90 mV. Ithas been shown that opening of potassium channels shifts the cellmembrane potential towards the equilibrium potassium membrane potential(E_(k)), resulting in hyperpolarization of the cell. Cook, N. S., Trendsin Pharmacol. Sciences, 9, pp. 21-28 (1988!. Hyperpolarized cells show areduced response to potentially damaging depolarizing stimuli. BKchannels which are regulated by both voltage and intracellular Ca²⁺ actto limit depolarization and calcium entry and may be particularlyeffective in blocking damaging stimuli. Therefore cell hyperpolarizationvia opening of BK channels may result in protection of neuronal cellsunder ischemic conditions.

The role of potassium channels in the operation of the smooth muscle ofthe human urinary bladder is discussed by S. Trivedi, et al. inBiochemical and Biophysical Research Communications, (1995), 213, No.2,pp. 404-409.

A range of synthetic and naturally occurring compounds with BK openingactivity have been reported. The avena pyrone extracted from avenasativa-common oats has been identified as a BK channel opener using alipid bi-layer technique International Patent application WO 93/08800,published May 13, 1993!. The flavanoid, Phloretin has been found toaffect the opening of Ca²⁺ -activated potassium channels in myelinatednerve fibers of Xenopus laevis using outside-out patches Koh, D- S., etal., Neuroscience Lett., 165, pp. 167-170 (1994)!.

U.S. Pat. No. 3,971,803 issued to S. Rosenberger and K. Schwarzenbach onJul. 27, 1976, relates to compounds of Formula (i): ##STR2## wherein R₁is alkyl, cycloalkyl or aralkyl;

R₂ is hydrogen or R₁ ;

R₃ is hydrogen or C₁₋₄ alkyl;

Y and Z are independently O or S;

R₄ is either (1), if m=1, C₁₋₈ alkylene, --C_(x) H_(2x) --Q--C_(y)H_(2y) -- (Q is O or S, x and y are integers whose sum is 2 to 4),phenylene, diphenylene or naphthalene or a ##STR3## group; or (2) ifm=2, alkylene, alkylene ether, alkylene thioether, diphenylene, ornapthalene. The compounds are antioxidants for organic polymers.

EPO 0-533276-A1 published on Mar. 24, 1993, shows compounds of Formula(ii): ##STR4## wherein one of P or Q is an ortho-substituted phenylgroup and the other a substituted benzyl. The Formula (ii) compounds aremiticides and insecticides.

A. E. Wilder Smith disclosed in Arzneim. Forsch. (1967) 67, No.17, pp.768-772, the preparation and study of compounds of Formula (iii):##STR5## wherein X is H or Cl and n is 1 or 2. The compounds havetuberculostatic properties. Formula (iii) compounds do not encompasssubstitution para to the hydroxyl group.

J. L. Romine, et al. in International Patent Application WO 98/04135,published Feb. 5, 1998, describe a series of diphenyl heterocycles ofthe Formula (iv): ##STR6## wherein Het is a heterocyclic moiety selectedfrom inter alia, oxadiazolone. The compounds are useful as modulators ofthe large conductance calcium-activated potassium channels and thestarting material for the preparation of the compounds of the presentinvention is described therein wherein Het is 1,3,4-oxadiazol-2(3H)-one,m=1 and n=0, R^(c) is chloro, R^(d) is trifluoromethyl and R^(a) |R^(b)|R^(e) is hydrogen.

International application WO 90/08128 published on Jul. 26, 1990,discloses compounds of the formula (iv): ##STR7## wherein D representsthe dehydrogenated residue of a hydroxy group or an NH-acidic group, mand p are 0 or 1, n is 1 to 4 and R₁, R₂, R₃ and R₄ are varioussubstituents. The compounds are prodrug derivatives of know biologicallyactive agents.

None of these references teach or suggest the novel compounds of thepresent invention.

SUMMARY OF THE INVENTION

The present invention provides novel benzoate derivatives of1,3,4-oxadiazolone having the general formula ##STR8## wherein R is asdefined below, or a nontoxic pharmaceutically acceptable salt or solvatethereof. The present invention also provides pharmaceutical compositionscomprising said benzoate derivatives and to the method of treatment ofdisorders sensitive to potassium channel opening activity such asischemia, stroke, convulsions, epilepsy, asthma, irritable bowelsyndrome, migraine, traumatic brain injury, spinal cord injury, sexualdysfunction, and urinary incontinence.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel benzoate derivatives of a 3-(5-chloro-2-hydroxyphenyl)methyl!-5-4-(trifluoromethyl)phenyl!-1,3,4-oxadiazol-2(3H)-one which is a potentopener of the large conductance, calcium-activated K⁺ -channels (BKchannel) and the novel derivatives have the general Formula ##STR9##wherein R is --NR¹ R² or ##STR10## in which ##STR11## is a counteranion; R¹ and R³ are hydrogen or C₁₋₄ alkyl; and

R² is hydrogen; C₁₋₄ alkyl; di(C₁₋₄ alkyl)aminoethyl; or R¹ and R² takentogether with the nitrogen atom to which they are attached, is aheterocyclic group selected from the group consisting of morpholine,piperidine, piperazine and N-(C₁₋₄ alkyl) piperazine;

or a nontoxic pharmaceutically acceptable salt or solvate thereof.

The present invention also provides a method for the treatment of orprotection from disorders which are mediated by opening of the largeconductance calcium-activated K⁺ channels (BK channels) in a mammal inneed thereof, which comprises administering to said mammal atherapeutically effective amount of a compound of Formula I or anontoxic pharmaceutically acceptable salt thereof. Preferably, thecompounds of Formula I are useful in the treatment of ischemia, stroke,epilepsy, convulsions, asthma, irritable bowel syndrome, migraine,traumatic brain injury, spinal cord injury, sexual dysfunction, andurinary incontinence and other disorders sensitive to BK channelactivating activity.

The term "C₁₋₄ alkyl" as used herein and in the claims (unless thecontext indicates otherwise) means straight or branched chain alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl. Preferably,these groups contain from 1 to 2 carbon atoms.

The term "a nontoxic pharmaceutically acceptable salt" and "counteranion" as used herein and in the claims is intended to include nontoxicacid addition salts and counter anions with inorganic and organic acids.Suitable salts with an acid and/or suitable counter anions of an acidare intended to include inorganic acid salts such as hydrochloride,hydrobromide, hydroiodide, sulfate, phosphate, and the like, and organicacid salts and/or counter anions of an acid such as formate, acetate,maleate, citrate, succinate, ascorbate, lactate, fumarate,methanesulfonate and tartrate which have been used to form salts ofbasic amines and quaternary amines.

Generally, pharmaceutically acceptable salts of the invention are thosein which the counter anion does not contribute significantly to thetoxicity or pharmacological activity of the salt. In some instances,they have physical properties which make them more desirable forpharmaceutical formulations, such as solubility, lack of hygroscopicity,compressibility with respect to tablet formation and compatibility withother ingredients with which the substance may be used forpharmaceutical purposes. The salts are routinely made by admixture of aFormula I compound with the selected acid, preferably by contact insolution employing an excess of commonly used inert solvents such aswater, ether, dioxane, methylene chloride, isopropanol, methanol,ethanol, ethyl acetate and acetonitrile. They may also be made bymetathesis or treatment with an ion exchange resin under conditions inwhich the appropriate ion of a salt of the substance of the Formula I isreplaced by another ion under conditions which allow for separation ofthe desired species such as by precipitation from solution or extractioninto a solvent, or elution from or retention on an ion exchange resin.

Certain compounds of the present invention including thepharmaceutically acceptable salts thereof can exist as solvated formsincluding hydrated forms such as monohydrate, dihydrate, hemihydrate,trihydrate, tetrahydrate and the like. The products may be truesolvates, while in other cases, the products may merely retainadventitious solvent or be a mixture of solvate plus some adventitioussolvent. It should be appreciated by those skilled in the art thatsolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention.

In the method of the present invention, the term "therapeuticallyeffective amount" means the total amount of each active component of thecomposition that is sufficient to show a meaningful patient benefit,i.e., healing of acute conditions characterized by openers of largeconductance calcium-activated K⁺ channels or increase in the rate ofhealing of such conditions. When applied to an individual activeingredient, administered alone, the term refers to that ingredientalone. When applied to a combination, the term refers to combinedamounts of the active ingredients that result in the therapeutic effect,whether administered in combination, serially or simultaneously. Theterms "treat, treating, treatment" as used herein and in the claimsmeans preventing or ameliorating diseases, tissue damage and/or symptomsassociated with dysfunction of cellular membrane polarization andconductance.

In another aspect, this invention provides water-soluble prodrugs of 3-(5-chloro-2-hydroxyphenyl)methyl!-5-4-(trifluoromethyl)phenyl!-1,3,4-oxadiazol-2(3H)-one which is describedin WO 98/04135. As used herein, the term prodrug denotes a derivative ofan active drug which is converted after administration back to theactive drug. More particularly, it refers to benzoate derivatives of1,3,4-oxadiazol-2(3H)-one compounds which may be active drugs and/orwhich are capable of undergoing hydrolysis of the ester moiety orcleavage of the ester so as to release active free drug. Thephysiologically hydrolyzable groups serve as prodrugs by beinghydrolyzed in the body to yield the parent drug per se, and thus, thewater-soluble prodrugs of the present invention are preferred foradministration of the parent drug.

In still another aspect, this invention provides a method for thetreatment of or protection from disorders which are mediated by openingof the large conductance calcium-activated K⁺ channels (BK channels) ina mammal in need thereof, which comprises administering to said mammal atherapeutically effective amount of a compound of Formula I or anontoxic pharmaceutically acceptable salt, solvate or hydrate thereof.Preferably, the compounds of Formula I are useful in the treatment ofischemia, stroke, convulsions, epilepsy, asthma, irritable bowelsyndrome, migraine, traumatic brain injury, spinal cord injury, urinaryincontinence, and sexual dysfunction in both men (erectile dysfunction,for example, due to diabetes mellitus, spinal cord injury, radicalprostatectomy, psychogenic etiology or any other cause) and women byimproving blood flow to the genitalia, especially the corpus cavernosumand other disorders sensitive to BK channel activating activity. Mostpreferably, the compounds of Formula I are useful in the treatment ofcerebral ischemia/stroke.

In still yet another aspect, this invention provides pharmaceuticalcompositions comprising at least one compound of Formula I incombination with a pharmaceutical adjuvant, carrier or diluent.

The compounds of Formula I may be prepared by various procedures such asthose illustrated herein in the examples, in the Reaction Schemes andvariations thereof which would be evident to those skilled in the art.The various prodrug compounds of Formula I may advantageously beprepared from the active drug substance of Formula II which is itselfprepared by the general procedure described in WO 98/04135 and inPreparation I and used as the starting material in the methodsillustrated in Reaction Scheme 1. ##STR12##

The preparation of 1,3,4-oxadiazol-2-(3H) derivatives of Formulas Ia andIb is illustrated in Reaction Scheme 1. The compound of Formula II istreated with either 4-chloromethylbenzoyl chloride or3-chloromethylbenzoyl chloride in the presence of a base such aspyridine in methylene chloride to provide the corresponding intermediateof Formula III. When it is desired to prepare compounds of Formula Iawherein R¹ and R² are as defined herein, the appropriate intermediate ofFormula III is treated with the desired amino compound in the presenceof a base such as potassium carbonate to afford the corresponding aminosubstituted benzoate esters of Formula Ia. The prodrug compounds ofFormula Ib are advantageously prepared by quaternarizing a compound ofFormula Ia with an alkylating agent such as methyl iodide, methylmethanesulfonate and the like to afford the quaternary amine of FormulaIb. Alternatively, the compounds of Formula Ib may be prepared directlyfrom the appropriate intermediate of Formula III by alkylation with atertiary amine in an inert organic solvent to afford the correspondingquaternary amine of Formula Ib.

In a preferred embodiment of the invention the compounds of Formula Ihave the Formula Ia ##STR13## wherein R¹ and R² each are independentlyhydrogen, C₁₋₄ alkyl or di(C₁₋₄ alkyl)aminoethyl; or R¹ and R² takentogether with the nitrogen atom to which they are attached, is aheterocyclic group selected from the group consisting of morpholine,piperidine, piperazine and N-(C₁₋₄ alkyl)piperazine; or a nontoxicpharmaceutically acceptable salt or solvate thereof. More preferably, R¹is methyl or ethyl and R² is methyl, ethyl or diethylaminoethyl. It ispreferred that R¹ and R₂ are morpholino, piperidino, or N-methylpiperazino and it is preferred that --CH₂ NR¹ R² is in the 4-position ofthe phenyl ring; or a nontoxic pharmaceutically acceptable salt orsolvate thereof.

In another preferred embodiment of the invention the compounds ofFormula I have the Formula Ib ##STR14## wherein R¹,R² and R³ arehydrogen or C₁₋₄ alkyl; and X is a counter anion or a nontoxicpharmaceutically acceptable salt or solvate thereof. More preferably,R¹,R² and R³ are methyl or ethyl; and X is chloro, bromo, sulfate,phosphate or methanesulfonate. It is most preferred that R¹, R² and R³are methyl; and X is chloro or methanesulfonate; or a nontoxicpharmaceutically acceptable salt or solvate thereof.

In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula I incombination with a pharmaceutical adjuvant, carrier or diluent.

In still another embodiment, this invention relates to a method oftreatment or prevention of disorders responsive to opening of potassiumchannels in a mammal in need thereof, which comprises administering tosaid mammal a therapeutically effective amount of a compound of FormulaI or a nontoxic pharmaceutically acceptable salt, solvate or hydratethereof.

In yet another embodiment, this invention relates to a method fortreating ischemia, convulsions, epilepsy, asthma, irritable bowelsyndrome, migraine, traumatic brain injury, spinal cord injury, male andfemale sexual dysfunction, urinary incontinence and especially stroke ina mammal in need thereof, which comprises administering to said mammal atherapeutically effective amount of a compound of Formula I or anontoxic pharmaceutically acceptable salt, solvate or hydrate thereof.

Biological Activity

Potassium (K⁺) channels are structurally and functionally diversefamilies of K⁺ -selective channel proteins which are ubiquitous incells, indicating their central importance in regulating a number of keycell functions Rudy, B., Neuroscience, 25, pp. 729-749 (1988)!. Whilewidely distributed as a class, K⁺ channels are differentiallydistributed as individual members of this class or as families. Gehlert,D. R., et al., Neuroscience, 52, pp. 191-205 (1993)!. In general,activation of K⁺ channels in cells, and particularly in excitable cellssuch as neurons and muscle cells, leads to hyperpolarization of the cellmembrane, or in the case of depolarized cells, to repolarization. Inaddition to acting as an endogenous membrane voltage clamp, K⁺ channelscan respond to important cellular events such as changes in theintracellular concentration of ATP or the intracellular concentration ofcalcium (Ca²⁺). The central role of K⁺ channels in regulating numerouscell functions makes them particularly important targets for therapeuticdevelopment. Cook, N. S., Potassium channels: Structure, classification,function and therapeutic potential. Ellis Horwood, Chinchester (1990)!.One class of K⁺ channels, the large-conductance Ca²⁺ -activated K⁺channels (BK or BK channels), is regulated by transmembrane voltage,intracellular Ca²⁺, and a variety of other factors such as thephosphorylation state of the channel protein. Latorre, R., et al., Ann.Rev. Physiol., 51, pp. 385-399 (1989)!. The large, singlechannel-conductance (generally >150 pS) and high degree of specificityfor K⁺ of BK channels indicates that small numbers of channels couldprofoundly affect membrane conductance and cell excitability.Additionally, the increase in open probability with increasingintracellular Ca²⁺ indicates involvement of BK channels in themodulation of Ca² +-dependent phenomena such as secretion and muscularcontraction. Asano, M., et al., J. Pharmacol. Exp. Ther., 267, pp.1277-1285 (1993)!.

Openers of BK channels exert their cellular effects by increasing theopen probability of these channels McKay, M. C., et al., J.Neurophysiol., 71, pp.1873-1882 (1994); and Olesen, S. -P., Exp. Opin.Invest. Drugs, 3, pp. 1181-1188 (1994)!. This increase in the opening ofindividual BK channels collectively results in the hyperpolarization ofcell membranes, particularly in depolarized cells, produced bysignificant increases in whole-cell BK-mediated conductance.

The ability of the compound of Preparation 1 to open BK channels andincrease whole-cell outward (K⁺) BK-mediated currents was assessed undervoltage-clamp conditions by determining their ability to increase clonedmammalian (mSlo or hSlo) BK-mediated outward current heterologouslyexpressed in Xenopus oocytes Butler, A., et al., Science, 261, pp.221-224 (1993); and Dworetzky, S. I., et al., Mol. Brain Res., 27,pp.189-193 (1994)!. The two BK constructs employed represent nearlystructurally identical homologous proteins, and have proven to bepharmacologically identical in our tests. To isolate BK current fromnative (background, non-BK) current, the specific and potent BKchannel-blocking toxin iberiotoxin (IBTX) Galvez, A., et al., J. Biol.Chem, 265, pp. 11083-11090 (1990)! was employed at a supramaximalconcentration (50 nM). The relative contribution of BK channels currentto total outward current was determined by subtraction of the currentremaining in the presence of IBTX (non-BK current) from the currentprofiles obtained in all other experimental conditions (control, drug,and wash). It was determined that at the tested concentration thecompound profiled did not effect non-BK native currents in the oocytes.The compound of Preparation 1 was shown in at least 5 oocytes at aconcentration of 1 μM to increase BK current to 126% of control ofIBTX-sensitive current. Recordings were accomplished using standardtwo-electrode voltage clamp techniques Stuhmer, W., et al., Methods inEnzymology, 207, pp. 319-339 (1992)!; voltage-clamp protocols consistedof 500-750 ms duration step depolarizations from a holding potential of-60 mV to +140 mV in 20 mV steps. The experimental media (modifiedBarth's solution) consisted of (in mM): NaCl (88), NaHCO₃ (2.4), KCl(1.0), HEPES (10), MgSO₄ (0.82), Ca(NO₃)₂ (0.33), CaCl₂ (0.41); pH 7.5.

A rapid screen to determine the ability of prodrugs to hydrolyze andrelease the drug (compound of Preparation 1) is conducted as follows. A1 mg/mL stock solution of the prodrug is prepared in distilled water oracetonitrile or PEG-400. Plasma from freshly collected rat or humanblood is used in this assay. To 1 mL of plasma at 37° C. was added 10 μLof stock solution of prodrug and mixed gently. Immediately after themixing, 100 μL of plasma was removed and quenched with 300 μL ofacetontrile (Zero time sample). Samples were also obtained at 30 minutesand quenched immediately. The quenched samples were centrifuged toobtain a clear supernatant for analysis. The stock solution, T=0 andT=30 samples were analyzed by a HPLC assay that separates the drug fromthe prodrug. Based on the relative peak areas of prodrug and drug inthese samples, different prodrugs are characterized as fast, moderateand slow release agents. For example, in this model, the compound ofExample 1 was dissolved in PEG-400 at a concentration of 1 mg/mL andincubated at 10 ug/mL in fresh rat plasma at 37° C. Analysis of thesolution 5 minutes after incubation indicated conversion of the compoundof Example 1 to the compound of Preparation 1.

To determine the ability of the compounds of the present invention toreduce cell loss resulting from neuronal ischemia, a standard focalcerebral ischemia is induced by permanent occlusion of the left middlecerebral artery (MCA) and common carotid artery (CCA) with one hourocclusion of the right CCA in the Wistar rat. The surgeries areperformed using the sub-temporal approach of A. Tamura, et al., J.Cereb. Blood Flow Metab., 1, pp. 53-60, (1981) and its modifications K.Osborne, et al., J. Neurol Neurosurg. Psychiatry, 50, pp. 402-410 (1987)and S. Menzies,et al., Neurosurgery, 31, pp. 100-107, (1992).!

The compound of Preparation 1 was evaluated in the focal stroke modelinvolving permanent occlusion of the left MCA (MCAO) and CCA (CCAO) andtemporary occlusion of the right CCA in the Wistar rat. This procedureresults in a reliably large neocortical infarct volume that is measuredby means of vital dye exclusion in serial slices through the brain 24hours after MCAO. In the present test, compounds were administered usingan i.v. or i.p. route of administration two hours after occlusion. Forexample, in this model the compound of Preparation 1 significantlyreduced the cortical infarct volume by about 18% when administeredintravenously (10 μg/kg) as a single bolus two hours after middlecerebral artery occlusion as compared to vehicle-treated (water)control.

The results of the above in vitro and in vivo tests demonstrate that thenovel 1,3,4-oxadiazol-2(3H)-one compounds of the present invention areuseful for the treatment of human disorders arising from dysfunction ofcellular membrane polarization and conductance and, preferably, areindicated for the treatment of ischemia, stroke, convulsions, epilepsy,asthma, irritable bowel syndrome, migraine, traumatic brain injury,spinal cord injury, sexual dysfunction, and urinary incontinence andother disorders sensitive to BK channel activating activity. Mostpreferably, the compounds of Formula I are useful in the treatment ofcerebral ischemia/stroke.

The compounds of Formula I or pharmaceutical compositions thereof areuseful in the treatment, alleviation or elimination of disorders orother disorders associated with the BK channels. Such disorders includeischemia, stroke, convulsions, epilepsy, asthma, irritable bowelsyndrome, migraine, traumatic brain injury, spinal cord injury, sexualdysfunction, and urinary incontinence and other disorders sensitive topotassium channel openers.

For therapeutic use, the pharmacologically active compounds of Formula Iwill normally be administered as a pharmaceutical composition comprisingas the (or an) essential active ingredient at least one such compound inassociation with a solid or liquid pharmaceutically acceptable carrierand, optionally, with pharmaceutically acceptable adjuvants andexcipients employing standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for oral,parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, placed in a hard gelatincapsule in powder or pellet form, or in the form of a troche or lozenge.The solid carrier may contain conventional excipients such as bindingagents, fillers, tableting lubricants, disintegrants, wetting agents andthe like. The tablet may, if desired, be film coated by conventionaltechniques. If a liquid carrier is employed, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule, sterile vehicle forinjection, an aqueous or non-aqueous liquid suspension, or may be a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Liquid preparations may contain conventional additives such assuspending agents, emulsifying agents, wetting agents, non-aqueousvehicle (including edible oils), preservatives, as well as flavoringand/or coloring agents. For parenteral administration, a vehiclenormally will comprise sterile water, at least in large part, althoughsaline solutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Particularlyuseful is the administration of a compound of Formula I directly inparenteral formulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound of Formula I according to the invention. See, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 17th edition, 1985.

The dosage of the compounds of Formula I to achieve a therapeutic effectwill depend not only on such factors as the age, weight and sex of thepatient and mode of administration, but also on the degree of potassiumchannel activating activity desired and the potency of the particularcompound being utilized for the particular disorder of diseaseconcerned. It is also contemplated that the treatment and dosage of theparticular compound may be administered in unit dosage form and that theunit dosage form would be adjusted accordingly by one skilled in the artto reflect the relative level of activity. The decision as to theparticular dosage to be employed (and the number of times to beadministered per day) is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical compositionthereof for a mammal, including man, suffering from, or likely to sufferfrom any condition as described herein is an amount of active ingredientfrom about 0.1 ng/kg to 10 mg/kg body weight. For parenteraladministration, the dose may be in the range of 0.1 ng/kg to 1.0 mg/kgbody weight for intravenous administration. The active ingredient willpreferably be administered either continuously or in equal doses fromone to four times a day. However, usually a small dosage isadministered, and the dosage is gradually increased until the optimaldosage for the host under treatment is determined.

However, it will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechoice of compound of be administered, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms.

The following examples are given by way of illustration and are not tobe construed as limiting the invention in any way inasmuch as manyvariations of the invention are possible within the meaning of theinvention.

DESCRIPTION OF SPECIFIC EMBODIMENTS

In the following examples, all temperatures are given in degreesCentigrade. Melting points were recorded on a Gallenkamp capillarymelting point apparatus temperatures are uncorrected. Proton magneticresonance (¹ H NMR) was recorded on a Bruker AC 300. All spectra weredetermined in the solvents indicated and chemical shifts are reported inδ units downfield from the internal standard tetramethylsilane (TMS) andinterproton coupling constants are reported in Hertz (Hz). Splittingpatterns are designated as follows: s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad peak; dd, doublet of doublet; bd,broad doublet; dt, doublet of triplet; bs, broad singlet; dq, doublet ofquartet. Infrared (IR) spectra using potassium bromide (KBr) weredetermined on a Perkin Elmer 781 spectrometer from 4000 cm⁻¹ to 400 cm⁻¹, calibrated to 1601 cm⁻¹ absorption of a polystyrene film and reportedin reciprocal centimeters (cm⁻¹ ). Low resolution mass spectra (MS) andthe apparent molecular (MH⁺) or (M-H)⁻ was determined on a Finnigen TSQ7000. High resolution mass spectra was determined on a Kratos MS50 inFAB mode using cesium iodide/glycerol as internal reference. The elementanalysis are reported as percent by weight.

The following preparations and examples illustrate procedures for thepreparation of starting materials, intermediates and methods for thepreparation of products according to this invention. It should also beevident to those skilled in the art that appropriate substitution ofboth materials and methods disclosed herein will produce the examplesillustrated below and those encompassed by the scope of this invention.

Preparation 1 3- (5-Chloro-2-hydroxyphenyl)methyl!-5-4-(trifluoromethyl)phenyl!-1,3,4-oxadiazol-2(3H)-one

STEP A. 5- 4-(Trifluoromethyl)phenyl!-1,3,4-oxadiazol-2(3H)-one

4-(Trifluoromethyl)benzoic acid hydrazide (commercially available fromMaybridge Chemicals) (5 g, 24.5 mmol) was taken up in THF (250ml)/triethylamine (2.7 ml, 26 mmol) under N₂ and1,1'-carbonyl-diimidazole (4.2 g, 26 mmol) added. The solution wasstirred for 18 h at 24° C., concentrated, and the residue was taken upin ethyl acetate, washed with 1 N HCl solution, sat'd NaHCO₃ solution,and brine prior to drying (MgSO₄). Concentration gave 5 g (89%) of thetitle compound from which a sample was recrystallized from diethylether/hexanes:

mp 214-216° C. MS m/z: 231 (MH⁺). IR (KBr) 3280, 1778, 1608, 1420, 1318,1170, 1114 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ7.87 (2H, d, J=8.3 Hz), 7.96 (2H,d, J=8.3 Hz), 12.77 (1H, br.s); Anal. Calcd. for C₉ H₅ F₃ N₂ O₂.064 H₂O: C, 46.74; H, 2.24; N, 12.11. Found: C, 47.07; H, 2.10; N, 12.34.

Step B. 3- (5-Chloro-2-methoxyphenyl)methyl!-5-4-(trifluoromethyl)-phenyl!-1,3,4-oxadiazol-2(3H)-one

5- 4-(Trifluoromethyl)phenyl!-1,3,4-oxadiazol-2(H)-one (11.75 g, 51mmol) and 5-chloro-2-methoxybenzylbromide N. Meanwell, et al., Bioorg.Med. Chem. Lett. 6, pp.1641-1646 (1996)! (12.0 g, 51 mmol) and 11.2 g(81 mmol) of potassium carbonate were added to CH₃ CN (300 ml) undernitrogen and potassium iodide (0.2 g, 1.2 mmol) was added. The solutionwas refluxed for 16 h, cooled, poured into water (1500 ml) and stirredvigorously. The precipitate was filtered to give a solid which wasrecrystallized from CH₃ CN to give 15.2 g (78%) of the title compound.

mp 144-145° C. MS(ESI)m/z: 385 (MH⁺). IR (KBr) 3440, 1782,1492, 1324,1248, 1168 cm⁻¹ ; ¹ H NMR (300 MHz, DMSO) 83.79 (3H, s), 4.91 (2H, s),7.07 (1H, d, J=8.8 Hz), 7.35-7.38 (2H, m), 7.88 (2H, d, J=8.4 Hz), 7.96(2H, d, J=8.2 Hz); Anal. Calcd. for C₁₇ H₁₂ CIF₃ N₂ O₃. 0.1 H₂ O: C,52.81; H, 3.19; N, 7.25. Found: C, 53.03; H, 3.20; N, 7.31.

Step C. 3- (5-Chloro-2-hydroxyphenyl)methyl!-5-4-(trifluoromethyl)-phenyl!-1,3,4-oxadiazol-2(3H)-one

3- (5-Chloro-2-methoxyphenyl)methyl!-5-4-(trifluoromethyl)-phenyl!-1,3,4-oxadiazol-2(3H)-one (15.2 g, 39.6mmol) was admixed with pyridine hydrochloride (19.7 g, 0.17 mol) andheated at 225° C. for 2 h. The hot solution was poured into 800 ml of 1N HCl and the mixture was stirred for 10 min. The solid was collected,washed with 1 N HCl and dried at 80° C. under vacuum to afford 13.1 g ofan off-white solid. Recrystallization from acetonitrile gave 10.8 g ofthe title compound as fluffy needles, mp 217-218° C. MS m/z: 371 (MH⁺).

IR (KBr) 3354, 1762, 1500, 1324, 1068 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 4.98(2H, s), 6.84 (1H, d, J=8.7 Hz), 7.20 (1H, dd, J=8.7 Hz, 2.6 Hz), 7.30(1H, d, J=2.5Hz), 7.89 (2H, d, J=8.6Hz), 7.97 (1H, d, J=8.6Hz), 10.11(1H, br.s); Anal. Calcd. for C₁₆ H₁₀ CIF₃ N₂ O₃ : C, 51.84; H, 2.72; N,7.56. Found: C, 51.88; H, 2.58; N, 7.57.

Preparation of Intermediates of Formula III

Preparation 2 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4-(chloromethyl)benzoate

A solution of 4-(chloromethyl)benzoyl chloride (2.24 g, 11.9 mmol) inmethylene chloride (25 mL) was added to a cold (0° C.) stirredsuspension of 3- (5-chloro-2-hydroxyphenyl)methyl!-5-4-(trifluoromethyl)phenyl!-1,3,4-oxadiazol-2(3H)-one (4.0 g, 10.8 mmol)and pyridine (0.96 mL, 11.9 mmol) in methylene chloride (25 mL). Thereaction mixture was allowed to warm to room temperature and stirredovernight. The reaction was quenched with 1 N HCl and extracted withethyl acetate (100 mL). The organic layer was separated and washed withsat'd NaHCO₃, water, brine and then dried (MgSO₄). Evaporation of thesolvent gave the crude product which was recrystallized from methylenechloride/hexanes to afford the title compound as white crystals (4.8 g,85%): mp 142-144° C.; MS m/e: 523 (MH⁺).

Anal. Calcd. for C₂₄ H₁₅ Cl₂ F₃ N₂ O₄.0.67 H₂ O: C, 53.84; H, 3.08; N,5.23. Found: C, 53.78; H, 2.97; N, 5.06. ¹ H NMR (CDCl₃): δ4.64 (s, 2H),4.96 (s, 2H), 7.19 (d, J=8.6 Hz, 1H), 7.40 (dd, J=2.5 Hz, 8.6 Hz, 1H),7.51-7.56 (m, 3H), 7.65 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.1 Hz, 2H), 8.21(dd, J=1.8 Hz, 6.6 Hz, 2H). IR (KBr, cm⁻¹): 3369, 1776, 1743, 1327,1170, 1112, 1068.

Preparation 3 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3-(chloromethyl)benzoate

The procedure of Preparation 2 was repeated except that3-(chloromethyl)benzoyl chloride was substituted for4-(chloromethyl)benzoyl chloride to yield the title compound.

¹ H NMR (CDCl₃) δ4.64 (s, 2H), 4.97 (s, 2H), 7.20 (d, J=8.4 Hz, 1H),7.41 (dd, J=8.4, 2.5 Hz, 1H), 7.50-7.55 (m, 2H), 7.63-7.78 (m, 5H), 8.17(dt, J=7.8, 1.2 Hz, 1H), 8.24 (t, J=1.2 Hz, 1H). MS m/e: 523 (MH⁺).Anal. Calcd. for C₂₄ H₁₅ Cl₂ F₃ N₂ O₄ : C, 55.09; H, 2.89; N, 5.35.Found: C, 55.06; H, 2.78; N, 5.14.

General procedure for the preparation of 3- and 4-(aminomethyl)benzoateesters of Examples 1-9

A mixture of the 4-(chloromethyl)benzoate of Preparation 2 or the3-(chloromethyl)benzoate of Preparation 3, (1 eqt.), the appropriateamine (1.1 eqt.), K₂ CO₃ (1.2 eqt) and Nal (0.2 eqt) in acetone wasstirred at room temperature for 1-2 days. After evaporation of theacetone, the residue was partitioned between diethylether and water. Theorganic layer was dried over magnesium sulfate, filtered and rotaryevaporated to dryness to afford the free base. The free base wasredissolved in diethylether and anhydrous HCl in diethylether was added.The precipitated HCl salt was collected by filtration and purified byeither trituration or recrystallization.

EXAMPLE 1 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (diethylamino)-methylbenzoate hydrochloride

mp: 158-162° C. MS m/e: 560 (MH⁺). Anal. Calcd. for C₂₈ H₂₅ ClF₃ N₃O₄.HCl.0.5 H₂ O: C, 55.55; H, 4.50; N, 6.94. Found: C, 55.55; H, 4.64;N, 6.66. ¹ H NMR (DMSO-d₆): δ 1.25 (t, J=7.1 Hz, 6H), 3.07 (s, br, 4H),4.42 (d, J=5.3 Hz, 2H), 5.04 (s, 2H), 7.44 (d, J=8.7 Hz, 1H), 7.57 (dd,J=2.6 Hz, 8.7 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.79-7.90 (m, 6H), 8.22(d, J=7.1 Hz, 2H).

EXAMPLE 2 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (4-morpholinyl)-methyl)!benzoate hydrochloride

mp: 150-152° C. MS m/e: 574 (MH⁺). Anal. Calcd. for C₂₈ H₂₃ ClF₃ N₃O₅.HCl.1.0 H₂ O: C, 53.52; H, 4.17; N, 6.69. Found: C, 53.30; H, 3.85;N, 6.62. ¹ H NMR (DMSO-d₆): δ 3.1-3.2 (m, br, 4H), 3.6-3.8 (m, br, 2H),3.9-4.0 (m, br, 2H), 4.49 (s, br, 2H), 5.04 (s, 2H), 7.42 (d, J=8.7 Hz,1H), 7.57 (dd, J=2.4 Hz, 8.7 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.73-7.89(m, 6H), 8.24 (d, J=7.7 Hz, 2H), 10.8 (s, br, 1H).

EXAMPLE 3 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (1-piperidinyl)methyl!-benzoate hydrochloride

mp: 223-225° C. (dec.). MS m/e: 572 (MH⁺). Anal. Calcd. for C₂₉ H₂₅ ClF₃N₃ O₄.HCl: C, 57.25; H, 4.31; N, 6.91. Found: C, 56.88; H, 4.43; N,6.62. ¹ H NMR (DMSO-d₆): δ 1.6-1.9 (m, br, 6H), 2.8-3.0 (m, br, 2H),3.2-3.3 (m, br, 2H), 4.40(d, J=4.9 Hz, 2H), 5.04 (s, 2H), 7.43 (d, J=8.7Hz, 1H), 7.58 (dd, J=2.6 Hz, 8.7 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H),7.77-7.89 (m, 6H), 8.24 (d, J=8.3 Hz, 2H), 10.18 (s, br, 1H).

EXAMPLE 4 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (4-methyl-1-piperazinyl)methyl!benzoate dihydrochloride

mp: 243-246° C. MS m/e: 587(MH⁺). Anal. Calcd. for C₂₉ H₂₆ ClF₃ N₄O₄.2.0 HCl.0.5 H₂ O: C, 52.07; H, 4.37; N, 8.38. Found: C, 51.70; H,4.62; N, 8.73. ¹ H NMR (DMSO-d₆): δ 2.78 (s, br, 3H), 3.0-3.8 (m, br,10H), 5.01 (s, 2H), 7.42 (d, J=8.7 Hz, 1H), 7.57 (dd, J=2.4 Hz, 8.7 Hz,1H), 7.71 (d, J=2.5 Hz, 1H), 7.78-7.88 (m, 6H), 8.16 (d, J=7.5 Hz, 2H).

EXAMPLE 5 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- N- 2-(diethylamino)ethyl!-N-ethylamino!methyl!benzoatedihydrochloride

mp: 129-132° C. MS m/e: 631 (MH⁺). Anal. Calcd. for C₃₂ H₃₄ ClF₃ N₄O₄.2.0 HCl.2.5 H₂ O: C, 51.31; H, 5.52; N, 7.48. Found: C, 51.12; H,5.55; N, 7.71. ¹ H NMR (DMSO-d₆): δ 1.25 (t, J=7.2 Hz, 9H), 3.0-3.2 (m,br, 6H), 3.6 (s, br, 4H), 4.50 (m,1H), 4.63 (m,1H), 5.04 (s, 2H), 7.44(d, J=8.7 Hz, 1H), 7.58 (dd, J=2.6 Hz, 8.7 Hz, 1H), 7.72 (d, J=2.5 Hz,1H), 7.81-7.91 (m, 6H), 8.22 (m, 2H), 10.7 (s, br, 1H), 11.5 (s, br,1H).

EXAMPLE 6 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- (diethylamino)methyl!-benzoate hydrochloride

mp: 196-197° C. (dec.). MS m/e: 560 (MH⁺). ¹ H NMR (DMSO-d₆): δ 1.23 (t,J=7.2 Hz, 6H), 3.06 (br m, 4H), 4.39 (d, J=5.4 Hz, 2H), 5.05 (s, 2H),7.44 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.4 Hz, 1H), 7.65-7.89 (m, 6H),8.01 (d, J=7.8 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.40 (s, 1H), 10.44 (br,1H). Anal. Calcd. for C₂₈ H₂₅ ClF₃ N₃ O₄.HCl: C, 56.39; H, 4.39; N,7.05. Found: C, 55.40; H, 4.31; N, 6.83.

EXAMPLE 7 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- (4-morpholinyl)methyl!-benzoate hydrochloride

mp: 226-227° C. MS m/e: 574 (MH⁺). ¹ H NMR (DMSO-d₆) δ 3.12-3.25 (br m,4H), 3.72-3.96 (br m, 4H), 4.43 (br, 2H), 5.05 (s, 2H), 7.43 (d, J=8.7Hz, 1H), 7.58 (dd, J=8.7, 2.4 Hz, 1H), 7.66-7.88 (m, 6H), 7.99 (d, J=7.8Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 8.38 (s, 1H). Anal. Calcd. for C₂₈ H₂₃ClF₃ N₃ O₅.HCl: C, 55.09; H, 3.96; N,6.88. Found: C, 54.09; H, 3.97; N,6.59.

EXAMPLE 8 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- (4-methyl-1-piperazinyl)methyl!benzoate dihydrochloride

mp: 245-247° C. (dec.). MS m/e: 587 (MH⁺). ¹ H NMR (DMSO-d₆) δ 2.50 (brs, 4H), 2.78 (br s, 3H), 3.20-3.70 (br m, 4H), 4.19 (br, 2H), 5.04 (s,2H), 7.42 (d, J=8.7 Hz, 1H), 7.55-7.94 (m, 10H), 8.37 (d, J=7.8 Hz, 1H),8.68 (br, 1H). Anal. Calcd. for C₂₉ H₂₆ ClF₃ N₄ O₄.2HCl: C, 52.78; H,4.28; N, 8.49. Found: C, 50.08; H, 4.16; N, 7.88.

EXAMPLE 9 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- N- 2-(diethylamino)ethyl!-N-ethylamino!methyl!benzoatedihydrochloride

mp: 152-154° C. (dec.). MS m/e: 631 (MH⁺). ¹ H NMR (DMSO-d₆) δ 1.12 (brm, 9H), 3.49-3.60 (br m, 8H), 4.47-4.60 (br m, 2H), 5.06 (s, 2H), 7.44(d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.4 Hz, 1H), 7.69-7.88 (m, 6H), 8.07(d, J=7.8 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.49 (s, 1H), 10.92 (br, 1H),11.49 (br, 1H). Anal. Calcd. for C₃₂ H₃₄ ClF₃ N₄ O₄.2HCl: C, 54.59; H,5.15; N, 7.96. Found: C, 52.56; H, 5.20; N, 7.71.

EXAMPLE 10 4- 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenoxy!carbonyl!phenyl!-methyl!trimethylammonium chloride

A solution of 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4-(chloromethyl)benzoate (0.3 g, 0.573 mmol) in acetonitrile/ethylacetate (20 mL) was saturated with anhydrous trimethylamine. Thereaction mixture was stirred at room temperature for two days. Theprecipitate was collected and purified by recrystallization fromacetonitrile-ether to afford the title compound as a white solid (0.24g, 72%):

mp 145-150° C. (dec.). MS m/e: 546 (M⁺). Anal. Calcd. for C₂₇ H₂₄ Cl₂ F₃N₃ O₄.1.5 H₂ O: C, 53.21; H, 4.47; N, 6.89. Found: C, 52.97; H, 4.69; N,6.61. ¹ H NMR (DMSO-d₆): δ 3.08 (s, 9H), 4.69 (s, 2H), 5.04 (s, 2H),7.43 (d, J=8.7 Hz, 1H), 7.58 (dd, J=2.6 Hz, 8.7 Hz, 1H), 7.72-7.77 (m,3H), 7.82 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.7 Hz, 2H), 8.27 (d, J=8.3 Hz,2H).

EXAMPLE 11 3- 4-Chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenoxy!carbonyl!phenyl!-methyl!trimethylammonium chloride

The general procedure of Example 10 was repeated except the compound ofPreparation 2 was replaced with the compound of Preparation 3 to yieldthe title compound.

mp: 195-197° C. (dec.); MS m/e: 546 (M⁺). ¹ H NMR (DMSO-d₆) δ 3.06 (s,9H), 4.65 (s, 2H), 5.04 (s, 2H), 7.43 (d, J=8.7 Hz, 1H), 7.59 (dd,J=8.7, 2.5 Hz, 1H), 7.72-7.92 (m, 8H), 7.63-7.78 (m, 5H), 8.31 (m, 2H).Anal. Calcd. for C₂₇ H₁₄ Cl₂ F₃ N₃ O₄ : C, 55.68; H, 4.15; N, 7.21.Found: C, 54.65; H, 4.41; N, 7.01.

What is claimed:
 1. A compound of the formula ##STR15## wherein R is--NR¹ R² or ##STR16## in which ##STR17## is a counter anion; R¹ and R³are hydrogen or C₁₋₄ alkyl; andR² is hydrogen; C₁₋₄ alkyl; di(C₁₋₄alkyl)aminoethyl; or R¹ and R² taken together with the nitrogen atom towhich they are attached, is a heterocyclic group selected from the groupconsisting of morpholine, piperidine, piperazine and N-(C₁₋₄alkyl)piperazine;or a nontoxic pharmaceutically acceptable salt orsolvate thereof.
 2. The compound of claim 1 wherein R is --NR¹ R² or anontoxic pharmaceutically acceptable salt or solvate thereof.
 3. Thecompound of claim 1 wherein R is ##STR18## or a nontoxicpharmaceutically acceptable salt or solvate thereof.
 4. The compound ofclaim 2 wherein R¹ and R² are methyl or ethyl or a pharmaceuticallyacceptable salt or solvate thereof.
 5. The compound of claim 3 whereinR¹, R² and R³ are methyl or ethyl or a pharmaceutically acceptable saltor solvate thereof.
 6. The compound of claim 1 wherein R¹ and R² takentogether with the nitrogen atom to which they are attached, ismorpholine or a pharmaceutically acceptable salt or solvate thereof. 7.The compound of claim 1 wherein R¹ and R² taken together with thenitrogen atom to which they are attached, is piperidine or apharmaceutically acceptable salt or solvate thereof.
 8. The compound ofclaim 1 wherein R¹ and R² taken together with the nitrogen atom to whichthey are attached, is N-methyl piperazine or a pharmaceuticallyacceptable salt or solvate thereof.
 9. The compound of claim 1 whereinR¹ is ethyl and R² is diethylaminoethyl or a pharmaceutically acceptablesalt or solvate thereof.
 10. The compound of claim 1 selected from thegroup consisting of:4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (diethylamino)methylbenzoate hydrochloride; 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (4-morpholinyl)methyl)!benzoate hydrochloride; 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (1-piperidinyl)methyl!benzoate hydrochloride; 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (4-methyl-1-piperazinyl)methyl!benzoate dihydrochloride; 4-chloro-2-5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- N- 2-(diethylamino)ethyl!-N-ethylamino!methyl!benzoatedihydrochloride; 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- (diethylamino)methyl!benzoate hydrochloride; 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- (4-morpholinyl)methyl!benzoate hydrochloride; 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- (4-methyl-1-piperazinyl)methyl!benzoate dihydrochloride; 4-chloro-2-5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl3- N- 2-(diethylamino)ethyl!-N-ethylamino!methyl!benzoatedihydrochloride; 4- 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenoxy!carbonyl!phenyl!methyl!trimethylammonium chloride; and 3- 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenoxy!carbonyl!phenyl!methyl!trimethylammoniumchloride;or a pharmaceutically acceptable salt or solvate thereof. 11.The compound of claim 10 selected from the group consistingof:4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (4-methyl-1-piperazinyl)methyl!benzoate dihydrochloride; 4-chloro-2-5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- N- 2-(diethylamino)ethyl!-N-ethylamino!methyl!benzoatedihydrochloride; and 4-chloro-2- 5-4-(trifluoromethyl)phenyl!-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl!methyl!phenyl4- (diethylamino)methyl!benzoate hydrochloride;or a pharmaceuticallyacceptable salt or solvate thereof.
 12. A pharmaceutical composition forthe treatment of disorders responsive to openers of the largeconductance calcium-activated potassium channels comprising atherapeutically effective amount of a compound as defined in claim 1 inassociation with a pharmaceutically acceptable carrier or diluent.
 13. Amethod for the treatment of disorders responsive to opening of the largeconductance calcium-activated potassium channels in a mammal in needthereof, which comprises administering to said mammal a therapeuticallyeffective amount of a compound as defined in claim
 1. 14. A method ofclaim 13 wherein said disorder is ischemia, stroke, convulsions,epilepsy, asthma, irritable bowel syndrome, migraine, traumatic braininjury, spinal cord injury, sexual dysfunction and urinary incontinence.15. The method of claim 13 wherein the disorder is stroke.